The BCM Human Genome Sequencing Center (HGSC) has developed a large scale, flexible DNA sequencing resource to solve major problems in human genetics and support clinical care. Technical excellence and innovation has allowed the use of multiple sequence platforms and the adaptation of the best sample resources and appropriate data models to match project requirements. In the first 18 months of the proposed timeline at least 1 petabase of DNA sequence will be generated, and 90% of capacity will be dedicated to cancer and human genetic studies. The remainder will be applied to comparative and metagenomics. All of this is made possible because of the HGSC's integrated high throughput data production pipeline that spans sample procurement and processing, sequence production, informatics, data analysis, and dissemination. The modular nature of this pipeline allows us to meet, or even exceed production expectations while at the same time provides flexibility to serve the diverse (and growing) needs of the genomics and biomedical research community. Overall one-half of the capacity will be dedicated to ongoing and emerging NHGRI programs with the remainder to a series of 11 innovative Center Initiated Projects (CIPs). The CIPs include solving the basis of selected common chronic human diseases, piloting a newborn screen and a national population-based health care model, deeply sampling human genetic diversity, identifying critical somatic mutations in rare and familiar cancers and the role of epigenomics in cancer therapy. For understanding common disease, we will develop future CIPs relevant to emerging priorities in human health such as Alzheimers disease. We will also provide a complete genome analysis of all the laboratory rhesus macaques in the USA, as well as study their microbiome. The virome in health and disease will be characterized and an educational program, based upon personal genome sequences will be delivered. The overall objectives, specific aims, and CIPs embodied in this proposal will transform biology through genomics and lead to a new phase of clinical applications.